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PCSK9 and HMG-CoA Reductase Inhibition and Cognitive Function
Quick Takes
- The absence of a relationship between PCSK9 inhibitors and the baseline and achieved LDL-C for memory and cognitive function was demonstrated in short-term clinical trials. The similar findings with genetic associations mimic potential long-lasting relationships between the drug class and adverse neurocognitive effects.
- The authors suggest the finding of an adverse effect of HMGCR neurocognitive function should be interpreted with caution given the limitation of Mendelian randomization, the irony that HMGCR improved memory performance, and the very minimal changes in variables that will need validation in long-term follow-up clinical studies.
- Also, the value of statins for primary and secondary prevention far exceeds the potential for loss of cognitive function in young persons and the elderly with no baseline cognitive issues—particularly considering that studies have shown that statin-associated cognitive side effects are reversed upon discontinuation.
Study Questions:
Does lipid-lowering therapy with statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition have adverse neurocognitive effects?
Methods:
The authors used single-nucleotide polymorphisms from recently released predominantly European ancestry-based genome-wide association studies of summary-level statistics of low-density lipoprotein cholesterol (LDL-C) and performed drug-target Mendelian randomization. The purpose was to examine the potential impact of PCSK9 and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibition across several cognitive-related outcomes in order to capture potential distinct cognition-related relationships including cognitive performance, memory performance, and reaction time. They also included structural neuroimaging data, biomarkers of Alzheimer’s disease, and Lewy body dementia risk to complement and extend previous drug-target studies by investigating biologically informed markers of dementia.
Results:
Using data from a combined sample of ~740,000 participants, there was an observed neutral cognitive profile related to genetic PCSK9 inhibition with no significant effects on cognitive performance, memory performance, or cortical surface area. Conversely, there were several adverse associations for HMGCR inhibition with lowered cognitive performance (beta = –0.082; 95% confidence interval [CI], –0.16 to –0.0080; p = 0.03), reaction time (beta = –0.00064; 95% CI, 0.00030 to 0.00098; p = 0.0002), and cortical surface area (beta = –0.18; 95% CI, –0.35 to –0.014; p = 0.03). Neither PCSK9 nor HMGCR inhibition impacted biomarkers of Alzheimer’s disease progression or Lewy body dementia risk. Consistency of findings across Mendelian randomization methods accommodating different assumptions about genetic pleiotropy strengthens causal inference.
Conclusions:
Using a wide range of cognitive function and dementia endpoints, there was no genetic evidence of an adverse PCSK9-related impact, suggesting a neutral cognitive profile. In contrast, there were observed neurocognitive effects related to HMGCR inhibition, which may well be outweighed by the cardiovascular benefits of statin use, but nonetheless may warrant pharmacovigilance.
Perspective:
What is the clinician to do? In a recent study using the ASPREE aspirin trial in the elderly, Zhou et al. (J Am Coll Cardiol 2021;77:3145-56), found no effect of statin therapy on cognitive decline and incident dementia in >18,000 persons followed for 4.5 years. Christie Ballantyne and Vijay Nambi wrote an accompanying editorial comment entitled, ‘Statins and Your Memory: “Forget” About It?’ The answer was no! Among the reasons were that the ASPREE study did not address statin dosing or LDL-C achieved and those elderly treated with statins were more likely to have comorbidities associated with cognitive decline.
Most importantly, those prescribing statins should use the information to encourage use of drugs that have a significant impact on LDL-C without concern for the decrease in LDL-C or target LDL-C and risk of cognitive decline.
Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Sleep Apnea
Keywords: Alzheimer Disease, Aspirin, Biomarkers, Cholesterol, LDL, Cognition, Cognition Disorders, Dementia, Dyslipidemias, Genetic Pleiotropy, Genome-Wide Association Study, Hydroxymethylglutaryl-CoA Synthase, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lewy Body Disease, Mendelian Randomization Analysis, Neuroimaging, Nucleotides, PCSK9 protein, human, Primary Prevention, Proprotein Convertase 9, Secondary Prevention, Subtilisins
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